Huntingtin-mediated axonal transport requires arginine methylation by PRMT6

Cell Rep. 2021 Apr 13;35(2):108980. doi: 10.1016/j.celrep.2021.108980.

Abstract

The huntingtin (HTT) protein transports various organelles, including vesicles containing neurotrophic factors, from embryonic development throughout life. To better understand how HTT mediates axonal transport and why this function is disrupted in Huntington's disease (HD), we study vesicle-associated HTT and find that it is dimethylated at a highly conserved arginine residue (R118) by the protein arginine methyltransferase 6 (PRMT6). Without R118 methylation, HTT associates less with vesicles, anterograde trafficking is diminished, and neuronal death ensues-very similar to what occurs in HD. Inhibiting PRMT6 in HD cells and neurons exacerbates mutant HTT (mHTT) toxicity and impairs axonal trafficking, whereas overexpressing PRMT6 restores axonal transport and neuronal viability, except in the presence of a methylation-defective variant of mHTT. In HD flies, overexpressing PRMT6 rescues axonal defects and eclosion. Arginine methylation thus regulates HTT-mediated vesicular transport along the axon, and increasing HTT methylation could be of therapeutic interest for HD.

Keywords: Huntington’s disease; PRMT2; PRMT6; arginine methylation; axonal transport; huntingtin; neurodegenerative diseases; neuronal death; protein arginine methyltransfearases; protein post-translational modification.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Arginine / metabolism
  • Axonal Transport / genetics*
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cell Death
  • Disease Models, Animal
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Epigenesis, Genetic*
  • Genes, Reporter
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Huntingtin Protein / genetics*
  • Huntingtin Protein / metabolism
  • Huntington Disease / genetics*
  • Huntington Disease / metabolism
  • Huntington Disease / pathology
  • Methylation
  • Mice
  • Mice, Transgenic
  • Neuromuscular Junction / genetics
  • Neuromuscular Junction / metabolism
  • Neuromuscular Junction / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein-Arginine N-Methyltransferases / genetics*
  • Protein-Arginine N-Methyltransferases / metabolism
  • Transport Vesicles / genetics
  • Transport Vesicles / metabolism*
  • Transport Vesicles / pathology

Substances

  • Brain-Derived Neurotrophic Factor
  • HTT protein, human
  • Huntingtin Protein
  • Nuclear Proteins
  • Protein Isoforms
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • BDNF protein, human
  • Arginine
  • PRMT6 protein, human
  • Protein-Arginine N-Methyltransferases